Our research has led us to postulate that major depression is associated, at least in part, with noradrenergic overdrive and a deficiency of synaptic norepinephrine. This postulate is based on the fact that biochemical alterations identified by us in the postmortem locus coeruleus (LC; brain norepinephrine neurons) of major depressive subjects can be produced experimentally in rats by treatments (e.g chronic stress) that elevate noradrenergic activity and deplete central norepinephrine. Also, repeated treatment of rats with antidepressant drugs reduces LC activity and downregulates specific proteins that we have found elevated in the LC of major depressive subjects. Together, these findings suggest that abnormalities in the LC are strongly associated with major depression. The central hypothesis of this proposal is that the noradrenergic pathobiology of depression is associated with elevated excitatory and reduced inhibitory inputs to the LC. A critical component of neuronal circuitry driving emotion-laden activation of the LC is corticotropin releasing factor (CRF) input from the amygdala. This circuit and other major "stress-sensitive" excitatory and inhibitory inputs to the LC, including substance P, glutamate, serotonin, and GABA, will be studied in the LC in postmortem brains from psychiatrically characterized subjects. Preliminary evidence of elevations of CRF and substance P input to the human LC in major depression is provided. Molecular pathways responsible for certain activation-induced biochemical changes in the LC include receptor-second messenger systems linked to gene expression through trans-activating factors. Potential disruption of these pathways in depression will be studied, emphasizing factors regulating long-term changes in LC gene expression. The overall goals of this application are to study neurotransmitter inputs that likely contribute to noradrenergic overdrive in major depression, and to investigate the molecular underpinnings of noradrenergic pathobiology. To achieve these goals, postmortem brain tissues from major depressive subjects (suicide and non-suicide), suicide victims lacking major depression, and carefully matched control subjects lacking major psychiatric disorders will be utilized. Diagnoses are made via a rigorous psychiatric/neurologic autopsy program under the direction of Dr. Craig Stockmeier.